The interferon inducing pathways and the hepatitis C virus

Eliane F Meurs, Pasteur Institute, Hepacivirus Unit, F-75015 Paris cedex, France

Adrien Breiman, Imperial College, Faculty of Medicine, Department of Virology, London W2 1PG, United Kingdom

Author contributions: All authors contributed equally to the work.

Correspondence to: Eliane F Meurs, Hepacivirus Unit, Department of Virology, Pasteur Institute, 28 rue du Dr Roux, 75724 Paris Cedex 15, France. rf.ruetsap@srueme

Telephone: +33-1-45688777 Fax: +33-1-40613012

Eliane F Meurs, Pasteur Institute, Hepacivirus Unit, F-75015 Paris cedex, France

Adrien Breiman, Imperial College, Faculty of Medicine, Department of Virology, London W2 1PG, United Kingdom

Author contributions: All authors contributed equally to the work.

Correspondence to: Eliane F Meurs, Hepacivirus Unit, Department of Virology, Pasteur Institute, 28 rue du Dr Roux, 75724 Paris Cedex 15, France. rf.ruetsap@srueme

Telephone: +33-1-45688777 Fax: +33-1-40613012

Received 2006 Dec 23; Revised 2006 Dec 28; Accepted 2007 Mar 21.

Abstract

The innate immune response is triggered by a variety of pathogens, including viruses, and requires rapid induction of type I interferons (IFN), such as IFNβ and IFNα. IFN induction occurs when specific pathogen motifs bind to specific cellular receptors. In non-professional immune, virally-infected cells, IFN induction is essentially initiated after the binding of dsRNA structures to TLR3 receptors or to intracytosolic RNA helicases, such as RIG-I /MDA5. This leads to the recruitment of specific adaptors, such as TRIF for TLR3 and the mitochondrial-associated IPS-1/VISA/MAVS/CARDIF adapter protein for the RNA helicases, and the ultimate recruitment of kinases, such as MAPKs, the canonical IKK complex and the TBK1/IKKε kinases, which activate the transcription factors ATF-2/c-jun, NF-κB and IRF3, respectively. The coordinated action of these transcription factors leads to induction of IFN and of pro-inflammatory cytokines and to the establishment of the innate immune response. HCV can cleave both the adapters TRIF and IPS-1/VISA/MAVS/CARDIF through the action of its NS3/4A protease. This provokes abrogation of the induction of the IFN and cytokine pathways and favours viral propagation and presumably HCV chronic infection.

Keywords: Toll-like receptor, RNA helicase, Mitochondrial adapter Cardif, TBK1/IKKepsilon, Interferon induction, HCV NS3A protease

Abstract

The sequence of the junction between the non structural proteins NS3 and NS4A (NS3/4A) , NS4A and NS4B (NS4A/4B), NS4B and NS5A (NS4B/5A) and NS5A and NS5B ( NS5A/5B) is given for 6 different HCV genotypes. The gene accession number (GI) for each is given in the Genotype column. For each sequence, the space indicates the NS3/4A-cleavage site. The consensus cleavage site is given in the text.

Footnotes

Supported by grants from the Agence Nationale pour la Recherche contre le SIDA

S- Editor Liu Y L- Editor Lutze M E- Editor Chen GJ

Footnotes

References

1. Le Bon A, Tough DFLinks between innate and adaptive immunity via type I interferon. Curr Opin Immunol. 2002;14:432–436.[PubMed][Google Scholar]
2. Brierley MM, Fish ENStats: multifaceted regulators of transcription. J Interferon Cytokine Res. 2005;25:733–744.[PubMed][Google Scholar]
3. de Veer MJ, Holko M, Frevel M, Walker E, Der S, Paranjape JM, Silverman RH, Williams BRFunctional classification of interferon-stimulated genes identified using microarrays. J Leukoc Biol. 2001;69:912–920.[PubMed][Google Scholar]
4. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, et al A Toll-like receptor recognizes bacterial DNA. Nature. 2000;408:740–745.[PubMed][Google Scholar]
5. Alexopoulou L, Holt AC, Medzhitov R, Flavell RARecognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001;413:732–738.[PubMed][Google Scholar]
6. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa CInnate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science. 2004;303:1529–1531.[PubMed][Google Scholar]
7. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer SSpecies-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004;303:1526–1529.[PubMed][Google Scholar]
8. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita TThe RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol. 2004;5:730–737.[PubMed][Google Scholar]
9. Andrejeva J, Childs KS, Young DF, Carlos TS, Stock N, Goodbourn S, Randall REThe V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter. Proc Natl Acad Sci USA. 2004;101:17264–17269.[Google Scholar]
10. Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K, Tsujimura T, Takeda K, Fujita T, Takeuchi O, et al Cell type-specific involvement of RIG-I in antiviral response. Immunity. 2005;23:19–28.[PubMed][Google Scholar]
11. Servant MJ, Grandvaux N, Hiscott JMultiple signaling pathways leading to the activation of interferon regulatory factor 3. Biochem Pharmacol. 2002;64:985–992.[PubMed][Google Scholar]
12. Sharma S, tenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott JTriggering the interferon antiviral response through an IKK-related pathway. Science. 2003;300:1148–1151.[PubMed][Google Scholar]
13. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM, Maniatis TIKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol. 2003;4:491–496.[PubMed][Google Scholar]
14. Yamamoto M, Sato S, Mori K, Hoshino K, Takeuchi O, Takeda K, Akira SCutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol. 2002;169:6668–6672.[PubMed][Google Scholar]
15. Oshiumi H, Matsumoto M, Funami K, Akazawa T, Seya TTICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction. Nat Immunol. 2003;4:161–167.[PubMed][Google Scholar]
16. Oshiumi H, Sasai M, Shida K, Fujita T, Matsumoto M, Seya TTIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta. J Biol Chem. 2003;278:49751–49762.[PubMed][Google Scholar]
17. Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K, Akira SToll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J Immunol. 2003;171:4304–4310.[PubMed][Google Scholar]
18. Jiang Z, Mak TW, Sen G, Li XToll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta. Proc Natl Acad Sci USA. 2004;101:3533–3538.[Google Scholar]
19. Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, Tschopp JRIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nat Immunol. 2004;5:503–507.[PubMed][Google Scholar]
20. Sasai M, Oshiumi H, Matsumoto M, Inoue N, Fujita F, Nakanishi M, Seya TCutting Edge: NF-kappaB-activating kinase-associated protein 1 participates in TLR3/Toll-IL-1 homology domain-containing adapter molecule-1-mediated IFN regulatory factor 3 activation. J Immunol. 2005;174:27–30.[PubMed][Google Scholar]
21. Häcker H, Redecke V, Blagoev B, Kratchmarova I, Hsu LC, Wang GG, Kamps MP, Raz E, Wagner H, Häcker G, et al Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature. 2006;439:204–207.[PubMed][Google Scholar]
22. Oganesyan G, Saha SK, Guo B, He JQ, Shahangian A, Zarnegar B, Perry A, Cheng GCritical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature. 2006;439:208–211.[PubMed][Google Scholar]
23. Schulz O, Diebold SS, Chen M, Näslund TI, Nolte MA, Alexopoulou L, Azuma YT, Flavell RA, Liljeström P, Reis e Sousa CToll-like receptor 3 promotes cross-priming to virus-infected cells. Nature. 2005;433:887–892.[PubMed][Google Scholar]
24. Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RAToll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med. 2004;10:1366–1373.[PubMed][Google Scholar]
25. Le Goffic R, Balloy V, Lagranderie M, Alexopoulou L, Escriou N, Flavell R, Chignard M, Si-Tahar MDetrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog. 2006;2:e53.[Google Scholar]
26. Kawai T, Sato S, Ishii KJ, Coban C, Hemmi H, Yamamoto M, Terai K, Matsuda M, Inoue J, Uematsu S, et al Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol. 2004;5:1061–1068.[PubMed][Google Scholar]
27. Honda K, Yanai H, Mizutani T, Negishi H, Shimada N, Suzuki N, Ohba Y, Takaoka A, Yeh WC, Taniguchi TRole of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc Natl Acad Sci USA. 2004;101:15416–15421.[Google Scholar]
28. Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, Takeshita F, Matsuda M, Coban C, Ishii KJ, Kawai T, et al Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction. J Exp Med. 2005;201:915–923.[Google Scholar]
29. Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, et al Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science. 2003;301:640–643.[PubMed][Google Scholar]
30. Edelmann KH, Richardson-Burns S, Alexopoulou L, Tyler KL, Flavell RA, Oldstone MBDoes Toll-like receptor 3 play a biological role in virus infections? Virology. 2004;322:231–238.[PubMed][Google Scholar]
31. Smith EJ, Marié I, Prakash A, García-Sastre A, Levy DEIRF3 and IRF7 phosphorylation in virus-infected cells does not require double-stranded RNA-dependent protein kinase R or Ikappa B kinase but is blocked by Vaccinia virus E3L protein. J Biol Chem. 2001;276:8951–8957.[PubMed][Google Scholar]
32. Honda K, Sakaguchi S, Nakajima C, Watanabe A, Yanai H, Matsumoto M, Ohteki T, Kaisho T, Takaoka A, Akira S, et al Selective contribution of IFN-alpha/beta signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection. Proc Natl Acad Sci USA. 2003;100:10872–10877.[Google Scholar]
33. Sun YW RIG-I, a human homolog gene of RNA helicase is induced by Retinoic Acid during the differentiation of acute promyelocytic leukemia cell.Thesis Shangai second Medical Univ.1997. [PubMed]
34. Cui XF, Imaizumi T, Yoshida H, Borden EC, Satoh KRetinoic acid-inducible gene-I is induced by interferon-gamma and regulates the expression of interferon-gamma stimulated gene 15 in MCF-7 cells. Biochem Cell Biol. 2004;82:401–405.[PubMed][Google Scholar]
35. Matikainen S, Sirén J, Tissari J, Veckman V, Pirhonen J, Severa M, Sun Q, Lin R, Meri S, Uzé G, et al Tumor necrosis factor alpha enhances influenza A virus-induced expression of antiviral cytokines by activating RIG-I gene expression. J Virol. 2006;80:3515–3522.[Google Scholar]
36. Kang DC, Gopalkrishnan RV, Wu Q, Jankowsky E, Pyle AM, Fisher PBmda-5: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties. Proc Natl Acad Sci USA. 2002;99:637–642.[Google Scholar]
37. Rothenfusser S, Goutagny N, DiPerna G, Gong M, Monks BG, Schoenemeyer A, Yamamoto M, Akira S, Fitzgerald KAThe RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J Immunol. 2005;175:5260–5268.[PubMed][Google Scholar]
38. Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K, Foy E, Loo YM, Gale M, Akira S, et al Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol. 2005;175:2851–2858.[PubMed][Google Scholar]
39. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, et al Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006;441:101–105.[PubMed][Google Scholar]
40. Gitlin L, Barchet W, Gilfillan S, Cella M, Beutler B, Flavell RA, Diamond MS, Colonna MEssential role of mda-5 in type I IFN responses to polyriboinosinic: polyribocytidylic acid and encephalomyocarditis picornavirus. Proc Natl Acad Sci USA. 2006;103:8459–8464.[Google Scholar]
41. Hornung V, Ellegast J, Kim S, Brzózka K, Jung A, Kato H, Poeck H, Akira S, Conzelmann KK, Schlee M, et al 5'-Triphosphate RNA is the ligand for RIG-I. Science. 2006;314:994–997.[PubMed][Google Scholar]
42. Pichlmair A, Schulz O, Tan CP, Näslund TI, Liljeström P, Weber F, Reis e Sousa CRIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates. Science. 2006;314:997–1001.[PubMed][Google Scholar]
43. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, Ishii KJ, Takeuchi O, Akira SIPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol. 2005;6:981–988.[PubMed][Google Scholar]
44. Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HBVISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell. 2005;19:727–740.[PubMed][Google Scholar]
45. Seth RB, Sun L, Ea CK, Chen ZJIdentification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell. 2005;122:669–682.[PubMed][Google Scholar]
46. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp JCardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature. 2005;437:1167–1172.[PubMed][Google Scholar]
47. Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y, Doi T, Shimotohno K, Harada T, Nishida E, et al Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways. Oncogene. 2003;22:3307–3318.[PubMed][Google Scholar]
48. Saha SK, Pietras EM, He JQ, Kang JR, Liu SY, Oganesyan G, Shahangian A, Zarnegar B, Shiba TL, Wang Y, et al Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif. EMBO J. 2006;25:3257–3263.[Google Scholar]
49. Lin R, Lacoste J, Nakhaei P, Sun Q, Yang L, Paz S, Wilkinson P, Julkunen I, Vitour D, Meurs E, et al Dissociation of a MAVS/IPS-1/VISA/Cardif-IKKepsilon molecular complex from the mitochondrial outer membrane by hepatitis C virus NS3-4A proteolytic cleavage. J Virol. 2006;80:6072–6083.[Google Scholar]
50. Sun Q, Sun L, Liu HH, Chen X, Seth RB, Forman J, Chen ZJThe specific and essential role of MAVS in antiviral innate immune responses. Immunity. 2006;24:633–642.[PubMed][Google Scholar]
51. Servant MJ, Grandvaux N, tenOever BR, Duguay D, Lin R, Hiscott JIdentification of the minimal phosphoacceptor site required for in vivo activation of interferon regulatory factor 3 in response to virus and double-stranded RNA. J Biol Chem. 2003;278:9441–9447.[PubMed][Google Scholar]
52. Peters RT, Liao SM, Maniatis TIKKepsilon is part of a novel PMA-inducible IkappaB kinase complex. Mol Cell. 2000;5:513–522.[PubMed][Google Scholar]
53. Bonnard M, Mirtsos C, Suzuki S, Graham K, Huang J, Ng M, Itié A, Wakeham A, Shahinian A, Henzel WJ, et al Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription. EMBO J. 2000;19:4976–4985.[Google Scholar]
54. Hemmi H, Takeuchi O, Sato S, Yamamoto M, Kaisho T, Sanjo H, Kawai T, Hoshino K, Takeda K, Akira SThe roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J Exp Med. 2004;199:1641–1650.[Google Scholar]
55. Harris J, Olière S, Sharma S, Sun Q, Lin R, Hiscott J, Grandvaux NNuclear accumulation of cRel following C-terminal phosphorylation by TBK1/IKK epsilon. J Immunol. 2006;177:2527–2535.[PubMed][Google Scholar]
56. Mattioli I, Geng H, Sebald A, Hodel M, Bucher C, Kracht M, Schmitz MLInducible phosphorylation of NF-kappa B p65 at serine 468 by T cell costimulation is mediated by IKK epsilon. J Biol Chem. 2006;281:6175–6183.[PubMed][Google Scholar]
57. Adli M, Baldwin ASIKK-i/IKKepsilon controls constitutive, cancer cell-associated NF-kappaB activity via regulation of Ser-536 p65/RelA phosphorylation. J Biol Chem. 2006;281:26976–26984.[PubMed][Google Scholar]
58. Kravchenko VV, Mathison JC, Schwamborn K, Mercurio F, Ulevitch RJIKKi/IKKepsilon plays a key role in integrating signals induced by pro-inflammatory stimuli. J Biol Chem. 2003;278:26612–26619.[PubMed][Google Scholar]
59. Wang N, Ahmed S, Haqqi TMGenomic structure and functional characterization of the promoter region of human IkappaB kinase-related kinase IKKi/IKKvarepsilon gene. Gene. 2005;353:118–133.[Google Scholar]
60. Hoofnagle JHCourse and outcome of hepatitis C. Hepatology. 2002;36:S21–S29.[PubMed][Google Scholar]
61. Heim MH, Moradpour D, Blum HEExpression of hepatitis C virus proteins inhibits signal transduction through the Jak-STAT pathway. J Virol. 1999;73:8469–8475.[Google Scholar]
62. Larrea E, Aldabe R, Molano E, Fernandez-Rodriguez CM, Ametzazurra A, Civeira MP, Prieto JAltered expression and activation of signal transducers and activators of transcription (STATs) in hepatitis C virus infection: in vivo and in vitro studies. Gut. 2006;55:1188–1196.[Google Scholar]
63. Melén K, Fagerlund R, Nyqvist M, Keskinen P, Julkunen IExpression of hepatitis C virus core protein inhibits interferon-induced nuclear import of STATs. J Med Virol. 2004;73:536–547.[PubMed][Google Scholar]
64. Pavio N, Lai MMThe hepatitis C virus persistence: how to evade the immune system? J Biosci. 2003;28:287–304.[PubMed][Google Scholar]
65. Foy E, Li K, Wang C, Sumpter R, Ikeda M, Lemon SM, Gale MRegulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003;300:1145–1148.[PubMed][Google Scholar]
66. De Francesco R, Tomei L, Altamura S, Summa V, Migliaccio GApproaching a new era for hepatitis C virus therapy: inhibitors of the NS3-4A serine protease and the NS5B RNA-dependent RNA polymerase. Antiviral Res. 2003;58:1–16.[PubMed][Google Scholar]
67. Dumont S, Cheng W, Serebrov V, Beran RK, Tinoco I, Pyle AM, Bustamante CRNA translocation and unwinding mechanism of HCV NS3 helicase and its coordination by ATP. Nature. 2006;439:105–108.[Google Scholar]
68. Bartenschlager RThe NS3/4A proteinase of the hepatitis C virus: unravelling structure and function of an unusual enzyme and a prime target for antiviral therapy. J Viral Hepat. 1999;6:165–181.[PubMed][Google Scholar]
69. Foy E, Li K, Sumpter R, Loo YM, Johnson CL, Wang C, Fish PM, Yoneyama M, Fujita T, Lemon SM, et al Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. Proc Natl Acad Sci USA. 2005;102:2986–2991.[Google Scholar]
70. Breiman A, Grandvaux N, Lin R, Ottone C, Akira S, Yoneyama M, Fujita T, Hiscott J, Meurs EFInhibition of RIG-I-dependent signaling to the interferon pathway during hepatitis C virus expression and restoration of signaling by IKKepsilon. J Virol. 2005;79:3969–3978.[Google Scholar]
71. Li K, Foy E, Ferreon JC, Nakamura M, Ferreon AC, Ikeda M, Ray SC, Gale M, Lemon SMImmune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc Natl Acad Sci USA. 2005;102:2992–2997.[Google Scholar]
72. Li XD, Sun L, Seth RB, Pineda G, Chen ZJHepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci USA. 2005;102:17717–17722.[Google Scholar]
73. Ferreon JC, Ferreon AC, Li K, Lemon SMMolecular determinants of TRIF proteolysis mediated by the hepatitis C virus NS3/4A protease. J Biol Chem. 2005;280:20483–20492.[PubMed][Google Scholar]
74. Lamarre D, Anderson PC, Bailey M, Beaulieu P, Bolger G, Bonneau P, Bös M, Cameron DR, Cartier M, Cordingley MG, et al An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature. 2003;426:186–189.[PubMed][Google Scholar]
75. Lin K, Perni RB, Kwong AD, Lin CVX-950, a novel hepatitis C virus (HCV) NS3-4A protease inhibitor, exhibits potent antiviral activities in HCv replicon cells. Antimicrob Agents Chemother. 2006;50:1813–1822.[Google Scholar]
76. Bogen SL, Arasappan A, Bennett F, Chen K, Jao E, Liu YT, Lovey RG, Venkatraman S, Pan W, Parekh T, et al Discovery of SCH446211 (SCH6): a new ketoamide inhibitor of the HCV NS3 serine protease and HCV subgenomic RNA replication. J Med Chem. 2006;49:2750–2757.[PubMed][Google Scholar]
77. Lindenbach BD, Evans MJ, Syder AJ, Wölk B, Tellinghuisen TL, Liu CC, Maruyama T, Hynes RO, Burton DR, McKeating JA, et al Complete replication of hepatitis C virus in cell culture. Science. 2005;309:623–626.[PubMed][Google Scholar]
78. Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, Habermann A, Kräusslich HG, Mizokami M, et al Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med. 2005;11:791–796.[Google Scholar]
79. Zhong J, Gastaminza P, Cheng G, Kapadia S, Kato T, Burton DR, Wieland SF, Uprichard SL, Wakita T, Chisari FVRobust hepatitis C virus infection in vitro. Proc Natl Acad Sci USA. 2005;102:9294–9299.[Google Scholar]
80. Yi M, Villanueva RA, Thomas DL, Wakita T, Lemon SMProduction of infectious genotype 1a hepatitis C virus (Hutchinson strain) in cultured human hepatoma cells. Proc Natl Acad Sci USA. 2006;103:2310–2315.[Google Scholar]
81. Blight KJ, McKeating JA, Rice CMHighly permissive cell lines for subgenomic and genomic hepatitis C virus RNA replication. J Virol. 2002;76:13001–13014.[Google Scholar]
82. Sumpter R, Loo YM, Foy E, Li K, Yoneyama M, Fujita T, Lemon SM, Gale MRegulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J Virol. 2005;79:2689–2699.[Google Scholar]
83. Marques JT, Devosse T, Wang D, Zamanian-Daryoush M, Serbinowski P, Hartmann R, Fujita T, Behlke MA, Williams BRA structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells. Nat Biotechnol. 2006;24:559–565.[PubMed][Google Scholar]
84. Loo YM, Owen DM, Li K, Erickson AK, Johnson CL, Fish PM, Carney DS, Wang T, Ishida H, Yoneyama M, et al Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection. Proc Natl Acad Sci USA. 2006;103:6001–6006.[Google Scholar]
85. Cheng G, Zhong J, Chisari FVInhibition of dsRNA-induced signaling in hepatitis C virus-infected cells by NS3 protease-dependent and -independent mechanisms. Proc Natl Acad Sci USA. 2006;103:8499–8504.[Google Scholar]
86. Vilasco M, Larrea E, Vitour D, Dabo S, Breiman A, Regnault B, Riezu JI, Eid P, Prieto J, Meurs EFThe protein kinase IKKepsilon can inhibit HCV expression independently of IFN and its own expression is downregulated in HCV-infected livers. Hepatology. 2006;44:1635–1647.[PubMed][Google Scholar]
87. Boya P, Larrea E, Sola I, Majano PL, Jiménez C, Civeira MP, Prieto JNuclear factor-kappa B in the liver of patients with chronic hepatitis C: decreased RelA expression is associated with enhanced fibrosis progression. Hepatology. 2001;34:1041–1048.[PubMed][Google Scholar]